Sj?gren's syndrome (SS) is an autoimmune disease of the oral system that leads to salivary gland destruction. Almost 3% of the U.S. population is affected by salivary gland hypofunction, a complex disorder resulting from disease etiologies, as well as being a common side effect of drug therapy. Saliva is an essential oral component needed for normal speech, taste, mastication, swallowing, and in protecting the hard and soft tissues of the oral cavity, however the etiology as why salivary glands are destroyed in diseases such as SS is still not known. Recent findings have provided strong evidence that like many inflammatory disorders, SS have its origin in an overactive immune response against salivary tissue and causing glandular destruction. However, the mechanisms underlying infiltration of immune cells and development of inflammatory response in salivary glands remain ill-understood. Thus, our goal is to understand the molecular events that contribute to the development of chronic salivary gland inflammation. Emerging evidence suggests that during inflammation, dead or dying host cells can release endogenous host factors called alarmins. They perform homeostatic functions when contained in intracellular compartments under normal conditions, but exhibit chemotactic and immune activating properties once released in extracellular milieu. Current evidence indicates that alarmins not only initiate but also amplify and sustain on-going inflammation. This underscores that identification and characterization of alarmins can direct the development of effective therapies against inflammatory disorders such as SS. Our ongoing studies have identified that galectin-3 and -9, host C-type lectins, normally found intracellularly, are extracellularly released and act as alarmins to exacerbate inflammatory responses during bacterial infection. Our preliminary studies revealed that both galectin-3 and -9 are abundantly expressed in salivary tissue of transgenic female mice overexpressing IL14? (IL14? mice) exhibiting SS associated phenotypes (mouse model of SS). Our central hypothesis is that galectin-3 and -9, once secreted into the extracellular milieu of salivary tissu, act as alarmins to exacerbate inflammatory responses by recruitment and activation of immune cells resulting in development of SS. To test our hypothesis we will: characterize galactin- 3 and -9 as novel alarmins in SS (AIM1), and determine the role of galectin-3 and -9 in salivary gland inflammation and degeneration using galectin-/- or IL14a/galectin-/- mice (AIM2). We expect that the proposed experiments will provide novel insights into the contribution of galectins as novel alarmins towards the development of pathogenesis of autoimmune diseases, including, but not limited to SS.